Pompholyx

Dishydrotic eczema
Precipitated by sweat - in high humidity conditions.
pruritic (intensely)
Small blisters
Management

• Cool compress
• Emolients
• Topical steroids

Diagnosis of Diabetes mellitus

[!TIP]Mnemonic: Seven - eleven

HbA1C > 6.5% is diagnosis of DM.

HbA1C should be avoided in pregnancy, children, haemoglobinopathies, haemolytic anaemia, HIV, untreated iron deficiency anaemia. (due to high turnover)
Abnormally low HbA1c can be caused by deteriorating renal function and weight loss.

Types of Thyroiditis

Thyroiditis typically causes a painful goiter.

Hashimoto thyroiditis (chronic autoimmune thyroiditis)

• COMMONEST CAUSE of hypothyroidism in iodine sufficient areas
• commoner in late middle aged women (x10 commoner in women)
• chronic automimmune thyroiditis - months to years.
• Chronic regeneration -> rubbery gland
• Associated with other autoimmune diseases (coeliac disease, vitiligo, type 1 DM)
• Predisposes to thyroid lymphoma - MALT lymphoma, to be specific.
  - In MALT lymphoma of thyroid, histology will show "extranodal marginal B cells".
  - MALT lymphoma = MALTOMA. (Occurs in stomach and thyroid gland, also salivary, lacrimal glands, lung)
• Histology: lymphocytic and plasma cell infiltration; Hurthle cells / aka oxyphil cells are also present.
  • Connective tissue is increased; less commonly to the extent of fibrosis. (the fibrosing variant -> but fibrosis does not extend outside the capsule, UNLIKE REIDEL THYROI THYROIDITIS
• Destruction is cell and antibody mediated.
• Management:
  • Thyroid hormone replacement.

Post partum thyroiditis.

• characteristic sequence of hyperthyroidism, which usually BEGINS one to four months after delivery and lasts two to eight weeks, followed by hypothyroidism, which lasts from approximately two weeks to six months, and then recovery

• 

• Acute thyroid damage -> release of T4 and T3 -> clinical and biochemical hyperthyroidism.

• Histology: infiltration with neutrophils and lymphocytes.

• Treatment: For pain and systemic symptoms: Aspirin / NSAID, failing which prednisolone. Pain should subside in 1 to 2 days.

• Recovery: The follicles regenerate and recovery is complete, through a transient hypothyroid stage, upto euthyroidism after a few months.
  

• Fibrosis extends into adjacent structures.

• Presentation: Dyspnoea, Dysphagia, hoarseness due to involvement of extrathyroidal structure by the fibrosis.

• Can be difficult to distinguish clinically from malignancy. Source

📑Azathioprine

• prodrug of mecaptopurine. (azathioprine -> mercaptopurine)
• mechanism: "Antimetabolite" - a drug which interferes with normal metabolism
• They inhibit purine metabolism and inhibit the 'wave of lymphoid proliferation'
• Therefore, they are cytotoxic
• Eliminated renally; reduce dose in AKI / renal impairment.
• Azathioprine is inactivated by xanthine oxidase. Patients on allopurinol require dose adjustment.
• Uses: renal allografts, crohn's disease
• Side effect: Bone marrow suppresion -> neutropenia

- Or with a *differentiating agent*. (**All trans retinoic acid**)
- has the t(15:17) translocation.

• Left shift of neutrophils. (but most cells will still be mature neutrophils; in CML, the proportion of immature cells is higher)

Background physiology of lymphocytes

Source-YouTube
Source-YouTube
Source-YouTube

• Different B cells are sensitive to different antigens.

• Binding of the pathogen to B cell receptors (which are membrane bound antibodies) causes B cell activation.

• But Activation of B cells also requires co-stimulation by (activated) TH cells. The B cell engulfs the pathogen via receptor mediated endocytosis and presents antigen on an MHC II molecule. A Th cell reactive to this antigen will arrive, bind and activate the B cell. (this makes B cells professional APCs)
  • To complicate things, b cells require two signals from the Th cell to become activated. There is also a less potent form of b cell activation - T cell independent activation which is dependent on B cell receptor crosslinking by antigents - but this method is less potent.
  • 
• After activation, B cells become effector cells or memory cells.
  • Effector cells renter the cell cycle and begin to proliferate and produces antibodies -> The antibody producing cells are called plasma cells
  • memory cells persist for memory.
• T cell also require activation and after activation they become effector and memory T cells.
• Th cells have CD4 receptors which bind to MHC Class II and get activated by APCs.
• Tc cells have CD8 receptors which bind to MCH Class I and get activated by 'all nucleated cells' which present an antigen.
• See [[2021 Basic Sciences July#HLA molecules|HLA Molecules]]
• After activation,
  • Effector Th cells -> activate B lymphocytes and secrete cytokines. ("alarm ringer") (one such cytokine is interferron gamma)
  • Effector Tc cells kill host cells.
  • Memory cells of both types persist.
• B cells can undergo activation and class switching.
  • T cell activation of B cells occurs in the lymph nodes.
  • naive B cells have membrane bound IgM and IgD.
  • First step after activation is somatic hypermutation. This generates B cells with various affinities for the same specific antigen. Low affinity B cells die and high affinity B cells survive.
  • The surviving high affinity B cells will undergo class witching.
  • once activated, they will produced IgG / M/ D etc. (rather than their naive state IgM). This is called isotype switching or class switching
  • Isotype switching is irreversible. It is done by altering DNA coding for the Fc region of antibodies.
  • Once class switching is done, the cell is called a plasma cell.
  • The type of antibody produced as a result of class witching depends on which cytokine was secreted by the activating T cell.
    • IL4 -> promotes IgG or IgE
    • TGF-beta -> IgG2b, IgA
    • IL5 -> IgA
    • IFN-gamma -> IgG2a or IgG3
  • Hyper IgM Syndrome: CD40 ligand signalling is defective; these individuals cannot class switch; they can only generate IgM. Individuals are immunocompromised.

Natural killer cells

• Are CD8+ T cells which do not have a TCR (T Cell receptor).
• They have receptors for MHC molecules. Stimulation of these receptors results in inhibition of killing.
• NK cells will kill any host cell that doesn't express MHC molecules.
• So any (host) cell that does not express adequate MHC molecules cannot inhibit NK cells and is killed by NK cells.
• 
• Source
• 
• Source

[!TIP] 2 minute summary: from MSD manuals
Chronic myeloid leukemia (CML) occurs when a pluripotent stem cell undergoes malignant transformation and clonal myeloproliferation, leading to a striking overproduction of mature and immature granulocytes. Initially asymptomatic, CML progression is insidious, with a nonspecific “benign” stage (malaise, anorexia, weight loss) eventually giving way to accelerated or blast phases with more ominous signs, such as splenomegaly, pallor, easy bruising and bleeding, fever, lymphadenopathy, and skin changes. Peripheral blood smear, bone marrow aspirate, and demonstration of the Philadelphia chromosome are diagnostic. Treatment is with tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, which significantly improve response and prolong survival. Myelosuppressive drugs (eg, hydroxyurea), stem cell transplantation, and interferon alfa are also sometimes used.

| Polycythemia | ❗Anaemia - may be symptomatic | |
| | Lymphadenopathy - only in blast crisis | |
| ❗Trilineage hypercellularity | Bone marrow : increased cellularity | |
| Mx : Aspirin and phlebotomy | TKI - b / intenstive chemotherapy like AML if blast phase occurs | |

Chronic lymphocytic leukemia features

[!INFO] 2 minute summary from MSD manuals.
Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of phenotypically mature malignant B lymphocytes. Primary sites of disease include peripheral blood, bone marrow, spleen, and lymph nodes. Symptoms and signs may be absent or may include lymphadenopathy, splenomegaly, hepatomegaly, fatigue, fevers, night sweats, unintentional weight loss, and early satiety. Diagnosis is by flow cytometry and immunophenotyping of peripheral blood. Treatment is delayed until symptoms develop and generally involves chemotherapy and immunotherapy. However, treatments are evolving, and first-line regimens may include targeted agents such as inhibitors of Bruton tyrosine kinase (Btk) and Bcl-2, with or without chemotherapy. CLL is considered incurable with current treatment.

Protozoan parasite.

The center of the spectrum consists of localized cutaneous leishmaniasis (LCL), which is the most common clinical presentation.
At the opposite end of the spectrum, diffuse cutaneous leishmaniasis (DCL) is caused by polyparasitic disease with a predominance of parasitized macrophages and no granulomatous inflammation.
This is the commonest form in Sri Lanka. Source

• Diagnosis is by demonstration of the parasite in a clinical specimen (usually skin) by histology, culture, or molecular analysis via polymerase chain reaction (PCR)
  
• AKA espundia.
• Mainly occurs in the 'new world'. (i.e North and south America).
  
• Treatment: pentavalent antimony salts (Sodium stibogluconate / melumine antimoniate) OR IV liposomal amphotericin B and IM paromomycin. Some patients develop post kalar-azar dermal leishmaniasis.
• Median time to onset is about 6 months to 2 years after treatment.
  Fever, headache, chills, and weakness and one or more swollen, painful lymph nodes (called buboes).

Follicular cells give rise to Papillary, follicular and anaplastic CA.
Parafollicular C cells -> Medullary CA. (C cells are neuroendocrine cells and they produce [[Hormone Physiology#Calcitonin|Calcitonin]]).

• Mnemonic: M for medullay and "middle" for parafollicuar cells in between follicles.
• Both papillary and follicular CA are 3 times commoner in women.
• Follicular develops at an older age.
• Thyroglobulin is produced by differentiated thyroid CA. It can be used as a marker of recurrent after total thyroid ablation.

Most cold nodules are due to benign processes (>90%)
Cold nodules have an approximately 5% risk of being cancerous.
--- simplified to--->

• Hot and cold nodules are mostly benign;
• Most nodules are cold nodules.
• Cold nodules have only a 5% risk of being malignant.
• Hot nodules have almost not malignant risk.
• 
  [[papillaryCAMnemonic.png]] <<-- have a look here!

• Papillary carcinoma is a slow-growing tumor (has good prognosis) that arises from the thyroxine (T4)- and thyroglobulin-producing follicular cells of the thyroid.
• Histology: Unencapsulated; Consist of neoplastic epithelium growing on fibro vascular cores.

• Psammoma bodies are seen in papillary CA. (concentric, lamellated microscopic calcium deposits. They can be seen in other cancers and some benign lesions as well)

• Haematogenous spread is rare but most common distant metastasis is to the lung.
• Factors which make a papillary CA high risk :
  • Hx of head and neck radiation, male sex, age < 18 or > 55, + other obvious ones.
  • Peak age for papillary carcinoma is 30-50 years.
• Are also usually cold nodules on radioiodine scan.
• Commoner in iodine deficient areas.
• Histology: encapsulated.
• Follicular cells have a solid, trabercular or follicular growth pattern.
• No characteristic nuclear features.
• Differentiated from benign adenomas by
  1. capsular invasion
  2. vascular invasion
• They arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically
• Follicular carcinomas have less tendency for local metz (nodes) but higher risk of distant mets.
• Distant mets for both types occur to lung and bone.

[!TIP] mnenonic: hurthel - turtle
Turtle cells have polygonal markings -> polygonal cells seen on histology

Hürthle cell carcinoma is a rare, more agrressive variant of follicular carcinoma. 5 year survival is 50 - 60%.
Composed of distinct looking polygonal cells with acidophillic cytoplasm.

So much so that there is a clinical distinction between identification of patients with familial MTC and diagnosis a new sporadic MTC.
RET proto-oncogene mutations are seen in all MTC syndromes.

Approximately 80% of individuals with a RET genetic variant will develop medullary thyroid cancer at some point in their lives.

• FTMC is a subtype of MEN2. FMTC patients have less probability of the other cancers of MEN2 but higher probability of medullary thyroid CA.
• Familial cases are multifocal and bilateral.
• Sporadic cases are unifolcal.
• Characteristic deposition of amyloid is seen in the tumour. <- A unique feature in thyroid malignancy.

In treatment of MEN, to avoid intra op hypertension, resection of pheochromocytoma should be done before MTC resection.
පර පා පි
පර මේ ෆි
මා මේ ෆි
[!TIP] Mnemonic: A for anaplastic and abyssmal
Occurs in older adults (60-70) -> older adult with a thyroid nodule could have a dangerous thyroid CA.
1 year survival is a dismal 20%. Median survival is 5-6 months.

• They will present with stridor or hoarseness.
• On histology, the tumour retains features og epithelial cells (presence of desmosomes) but there are large areas of necrosis and bleeding. There is high mitotic activity.

• Causes a sterile synovitis;
• Acute, asymmetrical, lower limb oligoarthritis days to weeks after infection such as dysentery or some sexually acquired infections.
• Triggers: dysentery due to salmonella, shigella, or sexually transmitted chlamydia or ureaplasma.
• Enthesitis causing plantar fascitis or achilles tendon enthesitis can occur.
• Sacroilitis and spondylitis can also develop. (Rember that HLAB27 is associated with Reactive arthritis AND psoriatic arthritis AND ankylosing sponlytis)
  • Penile ulcers - circinate balanitis
  • keratoderma blennorhagica - raised red plaques and pustules. Can occur on soles
• Dactylitis
• Many GU symptoms ?due to urethritis including clear discharge.
• Usually settles with treatment of the infection.

Mnemonic for HLA types and associations

HLA-A3:
3 looks like E.
AE - haemochromatosis

HLA-B51 - (B52 was a bomber in WW2)

diseases beging with B.
Behcet's disease

HLA-B27 - B 2 -> b is the second letter, A is the first leter.
All A's
Anki spondi
Arthrits - reactive and psoriatic
Anterior uveitis

HLA-DR2 (DR - doctor) 2 for two disease
Goodpasture
narcolepsy
(Good doctor is sleeping)

HLA-DR3 (3 looks like E)
Dry Eyes - Sjogrens - And everything starts with an S
Snakes - dermatitis herpetiformis (herpetologist - "herpet" means to do with snakes)
PBC - Seerrhosis

HLA-DR4
T1DM
Rheuamtoid arthritis (4 looks like A - RA -arthritis)

Glaucoma

Source Youtube
Managementof AACG - acetazolamid 500mg stat followed by pilocarpine
POAG - primary open angle glaucoma - associated with myopia (long eye ball) and not hypermetropia (short eye ball) like AACG.
Cup : Disk ratio > 0.7 is seen.